Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here, we tested whether REDD1 suppression makes glucocorticoid-based therapy of blood cancer safer. Unexpectedly, approximately 50% of top putative REDD1 inhibitors selected by bioinformatics screening of Library of Integrated Network-Based Cellular Signatures database (LINCS) were PI3K/Akt/mTOR inhibitors. We selected Wortmannin, LY294002, and AZD8055 for our studies and showed that they blocked basal and glucocorticoid-induced REDD1 expression. Moreover, all PI3K/mTOR/Akt inhibitors modified glucocorticoid receptor function shifting it toward therapeutically important transrepression. PI3K/Akt/mTOR inhibitors enhanced anti-lymphoma effects of Dexamethasone in vitro and in vivo, in lymphoma xenograft model. The therapeutic effects of PI3K inhibitor+Dexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that coadministration of LY294002 or Rapamycin with Dexamethasone protected skin against Dexamethasone-induced atrophy, and normalized RANKL/OPG ratio indicating a reduction of Dexamethasone-induced osteoporosis. Together, our results provide foundation for further development of safer and more effective glucocorticoid-based combination therapy of hematologic malignancies using PI3K/Akt/mTOR inhibitors.

中文翻译：

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通过 REDD1（发育和 DNA 损伤调节 1）抑制实现更安全的糖皮质激素受体靶向抗淋巴瘤治疗的新方法


糖皮质激素广泛用于治疗血液恶性肿瘤。不幸的是，长期使用糖皮质激素治疗通常会导致不良反应，包括皮肤和肌肉萎缩以及骨质疏松症。我们最近发现 REDD1（在发育和 DNA 损伤中受到调节 1）在类固醇萎缩中发挥着核心作用。在这里，我们测试了 REDD1 抑制是否使基于糖皮质激素的血癌治疗更安全。出乎意料的是，通过基于网络的细胞特征集成数据库（LINCS）的生物信息学筛选，大约 50% 的顶级推定 REDD1 抑制剂是 PI3K/Akt/mTOR 抑制剂。我们选择了 Wortmannin、LY294002 和 AZD8055 进行研究，结果表明它们可阻断基础和糖皮质激素诱导的 REDD1 表达。此外，所有 PI3K/mTOR/Akt 抑制剂都会改变糖皮质激素受体功能，使其转向具有治疗意义的反式阻抑。在淋巴瘤异种移植模型中，PI3K/Akt/mTOR 抑制剂在体外和体内增强地塞米松的抗淋巴瘤作用。 PI3K抑制剂+地塞米松组合的治疗效果从协同到协同，尤其是LY294002和雷帕霉素（用作先前表征的参考REDD1抑制剂）。我们发现，LY294002 或雷帕霉素与地塞米松共同给药可保护皮肤免受地塞米松诱导的萎缩，并使 RANKL/OPG 比率正常化，表明地塞米松诱导的骨质疏松症减少。总之，我们的结果为进一步开发使用 PI3K/Akt/mTOR 抑制剂的更安全、更有效的基于糖皮质激素的血液恶性肿瘤联合疗法奠定了基础。